The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Bleeding disorders are one of the most frequent gynecological problems. The causes of bleeding disorders, and their frequency in particular, vary depending on the age of the woman affected. In premenopause and perimenopause, the most frequent causes are hormonal as well as organic changes in the uterus such as myomas, adenomyosis uteri, or endometrial polyps. Coagulation defects cause increased bleeding, particularly in girls and young women, with no other recognizable cause.
Dysfunctional uterine bleeding can be treated surgically or medically. Surgical treatment includes endometrial ablation of the first and second-generation, and hysterectomy. Medical treatment, with the avoidance of possibly unnecessary surgery is generally the first treatment option employed to treat excessive bleeding and the only option for those who wish to preserve their reproductive function.
Despite the availability of a number of drugs, there is a general lack of an evidence-based approach, marked variation in practice and continuing uncertainty regarding the most appropriate therapy. Adverse effects and problems with compliance also undermine the success of medical treatment.
Drugs used in the therapy, mostly administered orally, consist of compounds reducing menstrual bleeding such as anti-fibrinolytic agents, non-steroidal anti-inflammatory drugs, prostaglandin synthesis inhibitors, progestogens, estrogen-progestogen combinations (oral contraceptives, e.g.), danazol, or analogues of gonadotrophin releasing hormone.
Plasminogen activators are a group of enzymes that cause fibrinolysis (the dissolution of clots). An increase in the levels of plasminogen activators has been found in the endometrium of women with heavy menstrual bleeding compared to those with normal menstrual loss. Plasminogen activator inhibitors, i.e. antifibrinolytic agents and especially tranexamic acid, have therefore been used as a treatment for heavy menstrual bleeding (see for example Tauber et al., Am J Obstet Gynecol. 1981 Jun. 1; 140(3):322-8, Wellington et al., Drugs. 2003; 63(13):1417-33, Lethaby et al., Cochrane Database Syst. Rev. 2000; (4):CD000249, Bongers et al., Maturitas. 2004 Mar. 15; 47(3):159-74). There has been a reluctance to prescribe the required high oral dosages of tranexamic acid due to possible side effects of the drugs such as an increased risk of thrombogenic disease (deep venous thrombosis). Antifibrinolytic therapy seems to cause a greater reduction in objective measurements of heavy menstrual bleeding but is not associated with an increase in side effects when compared to placebo or other medical therapies (NSAIDS, oral luteal phase progestagens and ethamsylate).
Danazol is a synthetic steroid with anti-estrogenic and anti progestogenic activity, and weak androgenic properties. Danazol suppresses estrogen and progesterone receptors in the endometrium, leading to endometrial atrophy (thinning of the lining of the uterus) and reduced menstrual loss and to amenorrhoea in some women. Danazol appears to be an effective treatment for heavy menstrual bleeding compared to other medical treatments, though it is uncertain whether it is acceptable to women (see for example Robins, Curr Womens Health Rep. 2001 December; 1(3):196-201, Beaumont et al., Cochrane Database Syst Rev. 2002;(2):CD001017). The oral use of danazol may be limited by its side effect profile, its acceptability to women and the need for continuing treatment. Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs but this did not appear to affect the acceptability of treatment.
Non-steroidal anti inflammatory drugs (NSAIDs) have proven useful in treating menorrhagia. NSAIDs reduce prostaglandin levels which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea and headaches (see for example Lethaby et al., Cochrane Database Syst Rev. 2002; (1):CD000400). Furthermore, they are taken only during the duration of the menses and are relatively cheap. As a group, NSAIDs have shown to be less effective than either tranexamic acid or danazol.
In addition to their contraceptive effect, combined oral contraceptive pills can also lead to substantial reductions in blood loss. Birth control pills contain synthetic forms of estrogen and progesterone, which prevent ovulation and, thereby, reduce endometrial build-up or thickness. As a result, most of the oral contraceptive users have lighter or minimal menstrual bleeding. Several synthetic progestogens can balance the effects of estrogen normally produced by the body and reduce endometrial growth. Luteinizing hormone releasing hormone (LHRH) and gonadotropin-releasing hormone (GnRH) or their analogues also appear to reduce menstrual blood loss (see for example Higham, Br J Hosp Med. 1991 January; 45(1):19-21).
Some efforts have been done to treat gynaecological bleeding irregularities by using local administration, for example intrauterine implants and intrauterine devices.
European patents EP 24779 and EP 24781 relate to a use of an amidine derivatives or a mixture of amidines in conjunction with an intrauterine device to produce an anti-proteolytic, an anti-fibrinolytic and anti-conceptive effect at a rate of 50 to 200 μg per day.
International patent application WO 2006028431 relates to an intrauterine implant and methods of use for creating fibrosis and resulting in amenorrhea. In particular, the device relates to an easily deployed intrauterine implant that readily and consistently reduces or eliminates abnormal intrauterine bleeding. In addition, the device is also used as a uterine marker for visualizing endometrial tissue thickness and potential changes. The methods of this invention relate to therapeutic approaches and additional contraceptive action.
International patent application WO 98/14169 is related to methods and compounds for treatment of abnormal uterine bleeding by using compounds that block uterine stromal cell response to angiogenic growth factors by interfering with the growth factors themselves, or by inhibiting or blocking receptors in the uterine epithelial or stromal cells to those growth factors. The response-blocking compounds are introduced into the body of a patient either systemically or locally to the uterus, e. g., via medicated intrauterine devices. However, the application does not describe any practical examples of using these intrauterine devices to introduce the compounds.
Finally, the levonorgestrel-releasing intrauterine system (LNG-IUS, for example MIRENA, developed by Bayer Schering Pharma Oy, Turku, Finland) has been shown to be effective as such in the treatment of heavy menstrual blood losses (see for example Luukkainen et al., Contraception. 1995 November; 52(5): 269-76; Andersson et al., Br J Obstet Gynaecol. 1990 August; 97(8):690-4; Moller et al., Hum Reprod. 2005 May; 20(5):1410-7; Lethaby et al., Cochrane Database Syst Rev. 2005 Oct. 19; (4):CD002126 and Cochrane Database Syst Rev. 2000; (2):CD002126). The LNG-IUS is a systemic hormonal contraceptive that provides an effective method for contraception and complete reversibility, and has an excellent tolerability record. The low dosage of levonorgestrel released by the system ensures minimal hormone-related systemic adverse effects, which gradually diminish after the first few months of use. It also gives users non-contraceptive health benefits. The local release of levonorgestrel within the endometrial cavity results in strong suppression of endometrial growth as the endometrium becomes insensitive to ovarian estradiol. The endometrial suppression is the reason for a reduction in the duration and quantity of menstrual bleeding and alleviates dysmenorrhea. By reducing menstrual blood loss, the LNG-IUS increases the body iron stores and can therefore be used to effectively treat menorrhagia. In many menorrhagic women, use of these IUSs can replace more invasive surgical methods such as hysterectomy or endometrial resection.
During the first months of use of an IUS irregularity in vaginal bleeding patterns is the most common clinical side effect. The irregularities may include an increase in the menstrual blood loss at cyclical periods, increased duration of bleeding at periods, and inter-menstrual bleeding and spotting. The pathogenesis of bleeding disturbances in IUS users is multifactorial and different etiologies have been suggested for different types of bleeding disturbances. Local increase in fibrinolytic activity is the most accepted cause for the increase of menstrual blood loss. The distortion of the endometrial vasculature by the presence of an intrauterine system can be explained by the direct effect of the device on the superficial vessels causing abrasions and erosions with possible irregular bleeding and/or the pressure distortion of the device, probably transmitted through endometrial tissue and resulting in endothelian injuries with the formation of fragile and dysfunctional blood vessels in the functional zone of the endometrium. The injury of vessel will lead to interstitial haemorrhage with the release of blood in an irregular pattern to the uterine cavity.
A significant number of users of the levonorgestrel-releasing intrauterine systems (LNG-IUS) expect not only contraceptive protection but also less menstrual problems. With LNG-IUS, there are undesired bleedings particularly during the first six to seven cycles after insertion. Complete amenorrhea is achieved only in part of the users even after long-term usage, and users often report about occasional bleedings, that are irregular and not predictable. Irregular bleeding is a common initial complaint among the users and long-term bleedings are often a reason for discontinuing the use of the system. Therefore there is still need for an intrauterine delivery system, the use of which would offer an improved and safe method of contraception and for suppressing abnormal and/or irregular bleeding and achieving a rapid induction of amenorrhea.